Abstract
Clinical signs in Parkinson’s disease (PD), including parkinsonian gait, are often asymmetric, but mechanisms underlying gait asymmetries in PD remain poorly understood. A translational toolkit, a set of standardized measures to capture gait asymmetries in relevant mouse models and patients, would greatly facilitate research efforts. We validated approaches to quantify asymmetries in placement and timing of limbs in mouse models of parkinsonism and human PD subjects at speeds that are relevant for human walking. In mice, we applied regression analysis to compare left and right gait metrics within a condition. To compare alternation ratios of left and right limbs before and after induction of parkinsonism, we used circular statistics. Both approaches revealed asymmetries in hind- and forelimb step length in a unilateral PD model, but not in bilateral or control models. In human subjects, a similar regression approach showed a step length asymmetry in the PD but not control group. Sub-analysis of cohorts with predominant postural instability-gait impairment and with predominant tremor revealed asymmetries for step length in both cohorts and for swing time only in the former cohort. This translational approach captures asymmetries of gait in mice and patients. Application revealed striking differences between models, and that spatial and temporal asymmetries may occur independently. This approach will be useful to investigate circuit mechanisms underlying the heterogeneity between models.
Highlights
Gait problems in Parkinson’s disease (PD) may manifest in multiple ways, including shuffling, freezing of gait, festination, and asymmetries[1,2,3,4]
Sites for intervention and to evaluate rehabilitation, neuromodulation or gene therapy treatments to selectively correct abnormal circuit function. For such a line of translational research to be successful, a methodology is required that captures asymmetries of gait metrics both in subjects with PD and in mouse models within a relevant speed range, i.e. at walking speeds in human subjects, as these relate to patient outcomes, and at speeds that represent walking or trotting in mice, where hindlimb coordination is similar to walking in humans
We used mouse models of parkinsonism that result in a unilateral (6-OHDA) or bilateral (MPTP) loss of striatal dopaminergic innervation, along with a control group to test the validity of three types of analysis, expecting gait asymmetries in the unilateral but not bilateral or control groups
Summary
Gait problems in Parkinson’s disease (PD) may manifest in multiple ways, including shuffling, freezing of gait, festination, and asymmetries[1,2,3,4]. Sites for intervention and to evaluate rehabilitation, neuromodulation or gene therapy treatments to selectively correct abnormal circuit function For such a line of translational research to be successful, a methodology is required that captures asymmetries of gait metrics both in subjects with PD and in mouse models within a relevant speed range, i.e. at walking speeds in human subjects, as these relate to patient outcomes, and at speeds that represent walking or trotting in mice, where hindlimb coordination is similar to walking in humans. We first measure asymmetries within a condition by adapting a regression analysis based method that we previously validated to quantify changes in gait metrics within a speed range that is clinically relevant, i.e. at walking speed[24] This method revealed that speed dependent gait signatures changed subtly in a unilateral 6-OHDA model and robustly in a systemic MPTP model. To determine whether similar methodologies detect asymmetries in gait metrics of subjects with PD but not control subjects and whether such asymmetries resemble those detected in PD mouse models, we applied this approach to gait datasets of human subjects with PD and healthy age matched controls
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